Alzheimer's disease (AD) is the leading cause of dementia and the fourth leading cause of death affecting four million Americans. There is no known cure. Our long term goal is to develop a drug which will effectively slow, halt or reverse the progression of AD to death. To do this, an animal model is essential for understanding the causes of the disease and for the development of drugs which effectively treat the disease. We propose to make a mouse model of the paired helical filament and/or neurofibrillary tangle (NFT) pathology that is associated with dementia, and with the neuronal degeneration observed in the brains of patients with AD. In humans, neurofibrillary tangles consists of bundles of paired helical filaments which are mainly composed of the tau protein. The amino acid sequence of mouse tau protein differs from human tau protein at many positions. We hypothesize that the pattern of mouse-TAU gene product expression is not equivalent to the pattern of human-TAU gene expression whose products are necessary, and perhaps sufficient, to provide conditions for paired helical filament and/or neurofibrillary tangle formation. This hypothesis is strongly supported by the observation that neurofibrillary tangles are observed in human brain neurons, particularly from patients with Alzheimer's, but have not been reported to be present in mouse brain. We will initially test this hypothesis by creating a mouse that expresses only human tau protein (Specific Aims 1, 2, 3). Should this be insufficient to produce PHF/NFT pathology, we will stress these animals in a variety of ways to predispose the formation and detection of PHF/NFT structures (Specific Aim 4).